Objective To perform a meta-analysis of randomized trials of early (prior to transfer
to the catheterization laboratory) vs late (at the time of PCI) intravenous
administration of Gp IIb/IIIa inhibitors in acute ST-segment elevation myocardial
infarction (STEMI).

Data Sources MEDLINE and the Cochrane Controlled Trials Register search of the literature
over the past 10 years; papers presented at major cardiac conferences; consultation
with national and international colleagues as well as Gp IIb/IIIa inhibitor
drug manufacturers; and text and journal article bibliographies.

Study Selection and Data Extraction We examined trials of randomized comparisons between early administration
at the point of initial contact (emergency department or ambulance) and late
administration (catheterization laboratory) of Gp IIb/IIIa inhibitors in STEMI.
Outcome data had to be available on both culprit artery patency evaluated
by Thrombolysis in Myocardial Infarction (TIMI) flow grades on admission and
mortality. Two authors independently reviewed abstracts or complete articles.
Six studies met inclusion criteria. Independent data extraction was performed
by 2 reviewers and confirmed by consensus.

Data Synthesis The 6 trials enrolled 931 STEMI patients treated with abciximab (3 trials)
or tirofiban (3 trials) in combination with primary PCI. TIMI grade 2 or 3
flow (41.7% [194/465 vs 29.8% [139/466]) as well as TIMI grade 3 flow (20.3%
[84/413] vs 12.2% [51/418]) were significantly more frequent in the early
group compared with the late group (odds ratio [OR], 1.69; 95% confidence
interval [CI], 1.28-2.22; P<.001; and OR, 1.85;
95% CI, 1.26-2.71; P<.001, respectively). The
early administration of Gp IIb/IIIa inhibitors was associated with a 28% reduction
of mortality from 4.7% to 3.4%, which was not significant but consistent with
similar trends for reinfarction and the composite ischemic end point.

Conclusions In a meta-analysis of 6 randomized trials, early administration of Gp
IIb/IIIa inhibitors in STEMI appeared to improve coronary patency with favorable
trends for clinical outcomes. These findings are supportive of a strategy
of facilitated PCI. Further evaluations in adequately powered large trials
are awaited to confirm the clinical benefit of this strategy.

Figures in this Article

Primary percutaneous coronary intervention (PCI) is widely regarded
as the reperfusion strategy of choice in ST-segment elevation myocardial infarction
(STEMI),1 but only a minority of STEMI patients
present directly to PCI centers, while the vast majority present initially
to their emergency ambulance service and/or to local hospitals and require
transfer to a tertiary center for primary PCI. Despite the attendant delay,
we confirmed in a recently published meta-analysis the superiority of transfer
for primary PCI over local thrombolysis.2 The
absence or negligible use of glycoprotein IIb/IIIa (Gp IIb/IIIa) antagonists
in the primary PCI arms of the studies of this meta-analysis may have reduced
the magnitude of benefit observed with primary PCI. Indeed, 5 randomized studies
have now shown a significant 30-day reduction in death or nonfatal MI or urgent
revascularization with Gp IIb/IIIa antagonists,3- 7 with
a pooled analysis confirming further a significant 34% reduction of death
or MI and a nonsignificant 26% reduction of mortality.8

The initial experience of exporting Gp IIb/IIIa inhibitors out of the
catheterization laboratory was described in the Abciximab before Direct Angioplasty
and Stenting in Myocardial Infarction Regarding Acute and Long-term Follow-up
(ADMIRAL) randomized study in which, for a subset of patients, treatment occurred
in the emergency department or even in the ambulance prior to arrival in the
catheterization laboratory.3 The magnitude
of the drug effect was increased dramatically in this subgroup compared with
the rest of the population treated later in the catheterization laboratory.

More recently, several small angiographic studies have been performed
to test the timing issue of Gp IIb/IIIa inhibitors in a randomized fashion.9- 14 Half
of these studies have been inconclusive on angiographic end points,11,13,14 and all have been
too small to make meaningful conclusions regarding clinical end points. We
therefore decided to perform a systematic meta-analysis.

METHODS

Study Objectives and Design

Our primary aim was to compare, in STEMI, immediate treatment with Gp
IIb/IIIa inhibitors prior to arrival in the catheterization laboratory vs
a later administration of Gp IIb/IIIa inhibitors just before primary PCI.
STEMI was defined according to the inclusion criteria of the trials concerned.
It was recognized that there would be heterogeneity in the studies and that
transfer times as well as patient management were likely to be variable. On
the other hand, by combining the studies, even if case-specific data were
not available, the statistical power to detect a difference in time effect
might be substantially increased.

Trial Search Strategy

We conducted a MEDLINE and Cochrane Controlled Trials Register search
of the literature to identify all randomized trials published in the last
10 years that compared early vs delayed administration of Gp IIb/IIIa inhibitors
in STEMI. In addition, we searched for papers presented at major cardiac conferences.
National and international colleagues as well as Gp IIb/IIIa inhibitor drug
manufacturers were consulted. Finally, text and journal article bibliographies
were hand searched. From these trials, specific "early vs late" studies were
identified, defined as those in which randomization occurred outside the catheterization
laboratory.

Study Selection and Data Extraction

We restricted our meta-analysis to trials that performed a randomized
comparison between early administration at the point of initial contact (emergency
department or ambulance) and late administration (catheterization laboratory)
of Gp IIb/IIIa inhibitors in STEMI. Outcome data had to be available on both
culprit artery patency evaluated on admission by TIMI flow grades and mortality.
Two authors (G.M., M.B.)independently reviewed abstracts or complete articles.
Only 6 nonoverlapping studies met the inclusion criteria. Independent data
extraction was performed by 2 reviewers and confirmed by consensus.

End Points and Definitions

The primary angiographic end point was the combined TIMI grade 2 and
3 flows on the first angiogram, which defined open culprit artery on admission.
TIMI grade 3 flow was also assessed separately. The primary clinical end point
was all-cause mortality at longest follow-up. The composite ischemic end point
at longest follow-up, as defined in each study, was also assessed separately.

Statistical Analysis

The results from each trial were those obtained on an intention-to-treat
basis. The meta-analysis was performed using the odds ratio (OR) as the parameter
of efficacy with a fixed effect model (Mantel-Haenszel),15 with
appropriate tests for association and heterogeneity. Finally, the number of
patients needed to be treated to avoid 1 event (NNT) was calculated for each
end point using the overall weighted risk difference (NNT = 1/[absolute risk
difference]).

The P value for significance of association
and heterogeneity tests was set at .05. The statistical analysis was performed
using EasyMA software.15

RESULTS

Trial Patient Characteristics and Study Designs

Six trials were identified with a design including randomization to
immediate vs delayed administration of Gp IIb/IIIa inhibitors for primary
PCI, in which randomization took place outside the catheterization laboratory.9- 14 The
trial names, acronyms, patient characteristics, and details of the study groups
are shown in Table 1.

Enrollment criteria of chest pain (<6 or <12 hours) with ST elevation
or new left bundle-branch block on the electrocardiogram were used throughout
(Table 1). Trial design was broadly
similar in all studies; however, there were some differences regarding site
of randomization: in 4 studies, randomization occurred in the emergency department
of the PCI center10- 12,14;
in 1 study, randomization was performed at the scene of presentation outside
the hospital and the drug was given during ambulance transportation13; and in the last study, patients could be enrolled
and randomized in the ambulance, at referring hospitals, or in the emergency
department of the PCI center but always before transfer to the catheterization
laboratory.9 One of the 6 randomized studies
was double-blind, placebo-controlled.9 The
same dose regimen of tirofiban was used throughout the 3 tirofiban studies
with a bolus of 10 µg/kg followed by a 0.15 µg/kg/min infusion,9- 11 and the same dose
regimen of abciximab was used throughout the 3 abciximab studies with an intravenous
bolus of 0.25 mg/kg followed by a 0.125 µg/kg/min infusion (to a maximum
of 10 µg/min).12- 14

Mortality data were available at 1 month follow-up in 3 studies,10,11,14 at 6-month follow-up
in 2 studies,12,13 and at 1-year
follow-up in the last study.9 The use of a
30-day composite ischemic end point of death, reinfarction, or urgent revascularization
was also consistent throughout the studies with a few differences between
trials, as indicated in Table 1.

Angiographic End Points

The proportion of patients with TIMI grade 2 or 3 flow was significantly
higher with an early administration of Gp IIb/IIIa inhibitors in only 3 of
the 6 trials.9,10,12 Combining
all 6 trials together, early administration of Gp IIb/IIIa inhibitors was
associated with a marked and highly significant increase in open infarct arteries
as indicated by a TIMI grade 2 or 3 flow rate of 41.7% vs 29.8% with a late
administration (OR, 1.69; 95% confidence interval [CI], 1.28-2.22; P<.001 [Figure 1]). There
was no evidence of heterogeneity, and the overall NNT was 8 for this primary
angiographic end point. Odd ratios were similar for the 2 tested drugs with
a nonsignificant interaction test for the type of drug.

The proportion of patients with TIMI grade 3 flow on the initial angiogram
was greatly increased in the early administration group (Figure 2). The overall NNT was 12 for achievement of TIMI grade
3 flow.

Clinical Outcomes

The mortality rates varied between trials, and none of the 6 trials
showed a significant difference between the 2 study groups. Combining the
trials, there was a 28% reduction in mortality in the early administration
group (16/467 [3.4%]) compared with the late administration group (22/466
[4.7%]), which did not reach statistical significance (Figure 3). There was no evidence of heterogeneity, and the ORs were
similar for the 2 tested drugs with a nonsignificant interaction test for
the type of drug. A similar favorable trend was found in the group receiving
GP IIb/IIIa inhibitors early for the composite ischemic end point (OR, 0.78;
95% CI, 0.51-1.20; P = .32) and for MI as individual
component of this end point (OR = 0.73, 95% CI, 0.31-1.77; P = .64).

Figure 3. Odds Ratios for Mortality With Early
vs Late Administration of Glycoprotein IIb/IIIa Inhibitors

Because small trials are more prone to be affected by publication bias,
we constructed funnel plots for both angiographic and clinical end points
that exhibited a fairly symmetrical distribution and convergence toward the
pooled effect when the weight of the trials increased, suggesting that publication
or selection bias was unlikely.

COMMENT

The attendant delay for primary PCI may limit its clinical benefit over
thrombolysis, especially when patients present within 3 hours after the onset
of symptoms.16,17 It has been
argued that "early pharmacologic facilitation" during the transfer period
to the catheterization laboratory may improve outcome, although the efficacy
of this strategy remains to date unproven. There is robust evidence for the
superiority of Gp IIb/IIIa inhibition over placebo in primary PCI.3- 8,18- 21 However,
the huge majority of patients recruited in Gp IIb/IIIa inhibition clinical
trials received treatment relatively late, at the time of PCI.

In the ADMIRAL study, the analysis of the prespecified subgroup that
received abciximab in the emergency department or in the ambulance showed
better outcomes than the group of patients receiving the drug later, suggesting
an advantage of "facilitation."3 However, to
definitively demonstrate facilitating efficacy requires randomization against
placebo, immediate administration of the study drug on presentation, and similar
pharmacologic treatment in both study arms during and after PCI. The 6 studies
we identified fulfilled these requirements.

The major finding of our meta-analysis is the demonstration of a probable
"facilitating" effect of Gp IIb/IIIa inhibitors for improving angiographic
patency of the culprit artery. TIMI flow on initial angiography is likely
of clinical importance since it has been shown to be a major determinant of
survival in primary PCI22 and a valid surrogate
end point for mortality in thrombolytic trials.23 The
early administration of Gp IIb/IIIa inhibitors was also associated with consistent
and favorable trends for mortality, reinfarction, and the composite ischemic
end point, although these differences remained nonsignificant.

Short time to treatment is a well-known factor for clinical benefit
with thrombolysis24 and with primary PCI.25- 28 It
appears that the same time-to-treatment paradigm applies to Gp IIb/IIIa inhibitors
when they are used in conjunction with primary PCI. This time factor in the
drug effect may also explain some of the discrepancies observed between primary
PCI trials that had different designs for the time of drug administration.3,5,8

The current meta-analysis has a number of limitations, including inevitable
clinical heterogeneity between trials and an overall sample size of only 931
patients, which is adequate for TIMI grade 2 or 3 flow (power of 97%) but
insufficient for clinical outcomes. Sensitivity analyses were also performed
and comparable results were obtained with a random effect model or when the
largest study was excluded from the meta-analysis. Our analyses were also
limited to short-term outcomes, but Gp IIb/IIIa inhibitor studies have often
demonstrated increasing survival benefit with longer follow-up.29,30 In
spite of the various limitations, however, the individual trials were in most
cases underpowered and the combined analysis allows more robust conclusions.

Our data support strongly several hypotheses developed in recent years
regarding what constitutes optimal myocardial reperfusion: first, the "open
artery hypothesis"; second, the "dethrombotic" effect of Gp IIb/IIIa inhibitors31,32; third, the key role of time to treatment
to improve outcomes; fourth, the concept of "facilitated" PCI, which still
needs to be confirmed for clinical outcome; and fifth, the need to develop
and/or consolidate prehospital/emergency department systems in the chain of
care provided for STEMI patients. Whether more aggressive pharmacologic approaches
using a full regimen of thrombolytics or reduced dose of lytics combined with
Gp IIb/IIIa inhibitors can open more arteries more rapidly with finally improved
clinical outcomes is so far unknown. Recent studies have suggested little
impact on infarct size and clinical outcomes of these new facilitating strategies,33 which now need to be tested in large-scale trials
such as the Safety and Efficacy of a New Thrombolytic (ASSENT)-4 and Facilitated
Intervention with Enhanced reperfusion Speed to Stop Events' (FINESSE) trials.

In conclusion, in STEMI patients treated with Gp IIb/IIIa inhibitors,
there appears to be significant angiographic benefit with favorable trends
for clinical outcome when treatment is started at first medical contact before
transfer to the catheterization laboratory. Further evaluations in adequately
powered large trials are awaited to confirm the clinical benefit of this strategy.

Fibrinolytic Therapy Trialists' (FTT) Collaborative Group. Indications for fibrinolytic therapy in suspected acute myocardial
infarction: collaborative overview of early mortality and major morbidity
results from all randomised trials of more than 1000 patients. Lancet.1994;343:311-322.PubMed

Fibrinolytic Therapy Trialists' (FTT) Collaborative Group. Indications for fibrinolytic therapy in suspected acute myocardial
infarction: collaborative overview of early mortality and major morbidity
results from all randomised trials of more than 1000 patients. Lancet.1994;343:311-322.PubMed

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